Prominent Lymphoplasmacytic Infiltrate Research Articles

Pulmonary squamous cell carcinoma and lymphoepithelial carcinoma - morphology, molecular characteristics and differential diagnosis.

Squamous cell carcinoma (SCC) comprises one of the major groups of non-small-cell carcinoma of the lung, and is subtyped into keratinising, non-keratinising and basaloid SCC. SCC can readily be diagnosed using histomorphology alone in keratinising SCC. Confirmatory immunohistochemical analyses should always be applied in non-keratinising and basaloid tumours to exclude differential diagnoses, most prominently adenocarcinoma and high-grade neuroendocrine carcinoma, which may have important therapeutic consequences. According to the World Health Organisation (WHO) classification 2015, the diagnosis of SCC can be rendered in resections of morphologically ambiguous tumours with squamous immunophenotype. In biopsies and cytology preparations in the same setting thecurrent guidelines propose a diagnosis of 'non-small-cell carcinoma, favour SCC' in TTF1-negative and p40-positive tumours to acknowledge a possible sampling bias and restrict extended immunohistochemical evaluation in order to preserve tissue formolecular testing. Most SCC feature a molecular 'tobacco-smoke signature' with enrichment in GG > TTmutations, in line with the strong epidemiological association of SCC with smoking. Targetable mutations are extremely rare but they do occur, in particular in younger and non- or light-smoking patients, warranting molecular investigations. Lymphoepithelial carcinoma (LEC) is a poorly differentiated SCC with a syncytial growth pattern and a usually prominent lymphoplasmacytic infiltrate and frequent Epstein-Barr virus (EBV) association. In this review, we describe the morphological and molecular characteristics of SCC and LEC and discuss the most pertinent differential diagnoses.

Syphilis in Hematopathology Practice: A Diagnostic Challenge.

Syphilis, a reemerging disease caused by the spirochete Treponema pallidum, is becoming more frequent in surgical pathology and hematopathology practices. Hematopathologists typically receive lymph node biopsies from patients with syphilis who have localized or diffuse lymphadenopathy. Occasionally, syphilis infection in the aerodigestive tract can show a prominent lymphoplasmacytic infiltrate and mimic lymphoma. Besides the varying and occasional atypical morphology, the fact that clinical suspicion tends to be low or absent when histologic evaluation is requested adds to the importance of making this diagnosis. To summarize histologic features of syphilitic lymphadenitis and syphilis lesions in the aerodigestive tract, and to review differential diagnosis and potential diagnostic pitfalls. Literature review via PubMed search. Characteristic histologic findings in syphilitic lymphadenitis include thickened capsule with plasma cell-rich inflammatory infiltrate, reactive follicular and paracortical hyperplasia with prominent lymphoplasmacytic infiltrate, and vasculitis. Lymph nodes, however, can show a number of other nonspecific histologic features, which frequently makes the diagnosis quite challenging. In the aerodigestive tract, syphilis is characterized by plasma cell-rich infiltrates. Immunohistochemistry for T pallidum is the preferred method for detecting spirochetes; however, this immunohistochemical stain shows cross-reactivity with other treponemal and commensal spirochetes. Differential diagnosis of syphilis in lymph nodes and the aerodigestive tract is broad and includes reactive, infectious, and neoplastic entities. Pathologists should be aware of the histologic features of syphilis and keep this challenging entity in the differential diagnosis.

A Novel CASC15-ALK and TFG-ROS1 Fusion Observed in Uterine Inflammatory Myofibroblastic Tumor.

The majority of inflammatory myofibroblastic tumors (IMTs) in the gynecologic tract occur in the uterine corpus and harbor anaplastic lymphoma kinase ( ALK ) rearrangement. Herein, we report 1 uterine IMT case with a novel fusion involving ALK and 1 uterine IMT case with ROS1 rearrangement. The ages of the patients were 56 and 57yr, respectively. The tumor size was 10.0 and 8.0cm, respectively. Both patients had stage IB disease. Histologically, the 2 IMT cases had classic morphologic features and predominantly comprised bland spindle cells with hypercellular (fascicular/storiform) and hypocellular (myxoid rich) areas admixed with variably prominent lymphoplasmacytic infiltration. Immunohistochemically, the ALK -rearranged case was positive for ALK , and the ROS1 -rearranged case was positive for ROS1 . Both cases were diffusely positive for desmin. The tumor cells were variably positive for estrogen receptor (1/2 cases, 50.0%) and progesterone receptor (1/2 cases, 50.0%). Targeted RNA sequencing revealed one case each with either a novel CASC15-ALK or TFG-ROS 1 fusion. We identified a novel ALK fusion partner CASC15 in IMT and described the first uterine IMT with a TFG-ROS1 fusion. This study improves our understanding of molecular events in IMT.

Unusual Diagnosis of Multiple Small Bowel Masses

Question: A 76-year-old man with hypertension and well-controlled diabetes presented to the hospital with poor appetite, abdominal distention, and intermittent nausea and vomiting for several weeks. He reported no fevers, sick contacts, or recent travel, but had an 18-pound unintentional weight loss during this time period with inability to tolerate solids for 4 weeks. Physical examination was notable for abdominal distension and tympany to percussion. Blood work showed a white blood cell count of 4,200/μL with a normal differential, hemoglobin of 13.1 g/dL, hematocrit of 38.2%, red blood cell count of 4.5 million/μL, and a platelet count of 239,000/μL. The metabolic profile was only notable for a potassium level of 2.8 mmol/L. There was no elevation in creatinine, calcium, or alkaline phosphatase. A computed tomography (CT) abdomen/pelvis scan without contrast showed multiple small bowel masses resulting in a small bowel obstruction, with the most proximal small bowel mass located in the third portion of the duodenum (Figure A). After NG tube decompression, enteroscopy was performed and identified an ulcerated mass near the ampulla measuring approximately 4 cm, and a single 1.5-cm ulcerated mass with adjacent edematous and friable mucosa in the third portion of the duodenum (Figure B). Duodenal biopsy showed small intestinal mucosa with prominent lymphoplasmacytic infiltrates in the lamina propria. Notably, these cells stained positive for CD138 on immunohistochemistry (Figure C). Serum protein electrophoresis and urine protein electrophoresis did not reveal any significant monoclonal spike or paraproteins. A subsequent bone marrow biopsy from the iliac crest was notable for an increased number of abnormal plasma cells, with less condensed nucleus and nucleolus. These abnormal plasma cells constituted 7% of the marrow (reference range, 0%–5%). The rest of the marrow differential consisted of the following: 63% myeloid cells (reference range, 30%–67%), 5% lymphocytes (reference range, 3%–17%), 25% erythroid cells (reference range, 10%–35%), and zero blasts (reference range, 0.3%–5%). There was no expression of kappa or lambda light chain. A subsequent whole-body positron emission tomography (PET)/CT showed no lytic lesions.

S3695 Collagenous Gastritis: A Rare Cause of Severe Iron Deficiency Anemia in a Basic Military Trainee

Introduction: Collagenous gastritis is a rare inflammatory disease characterized by deposition of a thick subepithelial band of collagen and associated inflammatory infiltrate. This disorder has a reported prevalence of 13 per 100,000 esophagogastroduodenoscopies (EGDs) with a female predominance. Two distinct clinical phenotypes have been described: adult-onset characterized by diffuse gastrointestinal involvement and diarrhea, and pediatric-onset manifesting with abdominal pain and anemia. We present an interesting case of pediatric-phenotype collagenous gastritis to highlight this poorly-recognized disorder. Case Description/Methods: A 19-year-old male basic military trainee was referred for evaluation of incidentally discovered iron deficiency anemia. He denied any symptoms, overt blood loss, or NSAIDs. Physical exam was unremarkable. Labs revealed hemoglobin of 9.3 g/dL, iron saturation 7% and ferritin 15 ng/mL. The patient underwent EGD and colonoscopy for further evaluation. EGD revealed a diffusely nodular appearance of the gastric mucosa with areas with suspected atrophy under narrow-band imaging (Figures 1A, B). Colonoscopy was normal. Biopsies returned with a non-specific chronic gastritis without H. pylori. Abdominal computed tomography and additional work up for autoimmune gastritis, fecal H. pylori antigen, syphilis, and heavy metals toxins were all normal. Decision was made to repeat EGD for additional tissue sampling, including cold snared samples. Repeat gastric biopsies with expert GI pathologist review revealed collagenous gastritis, characterized by subepithelial deposition of a thick (greater than 10 µm) collagen band and associated inflammatory infiltrate (Figures 1C, D). Patient was lost to follow up due to disqualification for military service. Discussion: Collagenous gastritis is an exceedingly rare heterogeneous disease process of poorly understood causes and pathogenesis, with autoimmune conditions, medication effects, and infections theorized to be responsible. Numerous treatments have been reported with variable effect, including antisecretory agents, corticosteroids, immunomodulators, and hypoallergenic diets, along with micronutrient supplementation. Due to its rarity, a high level of suspicion is required by gastroenterologists and pathologists based on clinical and endoscopic findings. Our case helps to bring awareness to collagenous gastritis, and emphasizes the potential value for repeat tissue sampling with expert pathologist review.Figure 1.: A: Diffusely nodular appearance of the gastric mucosa with areas. B: Narrow-band imaging reveals areas of suspected atrophy. C: Multiple fragments of gastric mucosa with a prominent lymphoplasmacytic infiltrate within the lamina propria and occasional foci of subepithelial collagen deposition (red arrows). [Hematoxylin & Eosin, 50× magnification]. D: On higher magnification a focus of subepithelial collagen deposition may be seen associated with epithelial injury indicated by loss of foveolar mucin and detachment of the surface epithelium. [Hematoxylin & Eosin, 200× magnification].

S3601 Gastric Inflammatory Myofibroblastic Tumor Presenting as Chronic Abdominal Pain in a Young Female

Introduction: Inflammatory Myofibroblastic Tumor (IMT) is a rare mesenchymal tumor, commonly seen in children and adolescents. Lung is the most common site. Here we present an extremely rare case of a gastric IMT in a 28 year old lady. Case Description/Methods: Pt presented with intermittent epigastric pain for 8 years. This was associated with bloating and regurgitation and weight loss.These symptoms worsened along with new symptoms of chest pain, Cardiology workup was unremarkable. CT abdomen with contrast ordered to investigate further revealed 3.9 cm x 3.6 cm intramural mass with smooth margin and areas of internal calcification, extending into the gastric lumen of the upper stomach at the left lateral fundal region. Pt was referred to a local gastroenterologist. EGD performed showed confirmation of the lesion. Pt was referred to surgical oncologist at tertiary care hospital. EGD performed with biopsy of the lesion showed Benign gastric mucosa with small separate fragment of gastric mucosa containing smooth muscle-like tissue consistent with a tangentially section muscularis mucosa vs benign smooth muscle mass. Given the inconclusive diagnosis, partial gastrectomy was performed after detailed discussion with the patient. Gross pathology showed a submucosal mass, corresponding to the serosa lesion, measuring 4.3 x 4.2 x 3.7 cm. Microscopic pathology showed spindle cells with variable Cellularity with prominent lymphoplasmacytic infiltrates along with dystrophic calcification and osseous metaplasia. There is regional expression of ALK-1,and regional subserosal expression of SMA and MSA. Lesional cells do not express CD117, DOG-1, and desmin. The immunoprofile supports interpretation of IMT. Patient was seen eight months post surgery with resolution of all the symptoms. (Figure) Discussion: Primary gastric IMT is extremely rare. There have been a handful of cases in literature. Gastric IMT is most commonly associated with abdominal pain and upper GI bleeding. Most common treatment is partial gastrectomy. There is some potential of IMT to turn into malignancy. IMT are associated with high local recurrence rates. There are no guidelines on surveillance though common consensus is to perform EGD 6 months to a year initially followed by increasing the interval later. As GI clinicians, we should be aware of these symptoms associated with IMT.Figure 1.: CT images and Histology.

A case of Lymphoplasmacyte-rich meningioma mimicking pachymeningitis

BackgroundLymphoplasmacyte-rich meningioma (LPRM) is a rare form of meningioma characterized by prominent lymphoplasmacytic infiltrates into the tumor. Report of flat growth of LPRM mimicking pachymeningitis is rare in the literature.Case presentationA 55-year-old female who suffered from episodes of headache and seizures has been diagnosed with pachymeningitis for 4 years because post contrast brain MRI demonstrated enhanced carpet-like dura lesion in the left frontal lobe. The lesion kept unchanged on yearly follow-ups until a recent brain MRI found the lesion grew significantly into a mass. The lesion was resected and pathology suggested LPRM.ConclusionLPRM may present as carpet-like growth pattern on MRI. Long-term follow-up in patients with pachymeningitis is necessary.

Medullary carcinoma of the colon: A comprehensive analysis of a large cancer database.

180 Background: Medullary carcinoma (MC) of the colon was described first in 1999 and is characterized by undifferentiated sheets of epithelial cells in a solid growth pattern with pushing borders and prominent lymphoplasmacytic infiltrates. It frequently shows microsatellite instability (MSI). However, the clinicopathological and survival outcomes between MC and the more common adenocarcinoma of the colon (AC) are not well defined in a large database. Therefore, we used a large national registry to explore the association of survival characteristics with sociodemographic, geographic, and disease variables in this cohort of patients. Methods: We sampled the National Cancer Database (NCDB) for colon cancer patients diagnosed with MC from 2004-2018. Multivariate cox regression models were used to compare hazard ratios for demographic, geographic, and disease characteristics. In addition, Kaplan-Meier survival plots were utilized to assess survival rate differences between MC and AC tumors located in the ascending, transverse, or descending colon. A p-value<0.05 was considered statistically significant. Results: Only 2,709 (0.29%) of the 922,667 patients with AC had MC. MC was seen in older patients than AC (76 vs. 69 years). MC was also more common in females than AC (72.5 vs. 49%). The most striking finding in our analysis was the predominance of poorly differentiated (63%) and undifferentiated (21.7%) pathologies in MC. This was in sharp contrast to AC, where 15.8% of patients were poorly differentiated, and only 2% were undifferentiated. Furthermore, undifferentiated and poorly differentiated MC tumors had a poor prognosis (HR 1.45, 95% CI 1.26-1.68, p<0.001 and HR 1.44, 95% CI 1.29-1.62, p<0.001 respectively) as compared to the other histological grades. Another notable finding in our analysis was the high prevalence of MSI in MC vs. AC (82.4% vs. 25.9%). Cecal MC (HR 1) had the worst prognosis of any colonic site. Left-sided MC tumors also had an inferior prognosis compared to AC (63.21 vs. 87.72 months), although not statistically significant (p=0.217). Conclusions: Colon cancer presenting as undifferentiated or poorly differentiated with associated MSI should raise the possibility of a medullary carcinoma diagnosis. However, given the rarity and difficulty in its pathological delineation, MC may remain underdiagnosed. In the modern treatment era, with the approval of immunotherapy for metastatic MSI colon cancer patients, survival and outcomes for metastatic MC may be improved.

Correlation between Peripheral Blood Eosinophilia and the Histopathological Changes in Nasal Mucosal in Chronic Rhinosinusitis

Background: Chronic rhinosinusitis(CRS) has emerged as one of the major causes of significant morbidity in otorhinolaryngology, as it is often noted to be refractory to medical management and has a tendency to recur post-surgery. Limited research has shown that peripheral eosinophilia is related to the presence of nasal polyps, the extent of the mucosal disease, the severity of tissue eosinophilia, and the risk of recurrence.
 Aim: This study aimed to establish the significance of peripheral blood eosinophilia, both differential (EC) and absolute eosinophil counts (AEC) - in adult CRS, to correlate the tissue eosinophilia and peripheral blood eosinophilia, and compare the observations in the two types of CRS with nasal polyp and without nasal polyp.
 Material and Methods: A total of 50 adult patients with CRS who underwent FESS were included in the study and were divided based on the presence (Group 1) or absence (Group 2) of peripheral blood eosinophilia.
 Results: There were equal number of cases of chronic rhinosinusitis with nasal polyp (CRSwNP) and without polyp (CRSsNP); 25 each. With regard to clinical features, Group 1 had a higher number of cases with nasal obstruction (p-value = 0.023), post-nasal drip (p-value = 0.035), and hyposmia (p-value = 0.021) when compared to Group 2. On histopathology, Group 1 had more areas of edema (p-value = 0.027), and mucous gland hyperplasia (p-value = 0.013) while Group 2 had prominent lymphoplasmacytic infiltrates (p-value = 0.035), neutrophilia (p-value = 0.047), and tissue infiltration of macrophages (p-value = 0.027). Tissue eosinophilia was present in 32 out of the total cases; 20 (71.43%) in Group 1 and 12 (53.33%) in Group 2. The group with tissue eosinophilia had significantly higher eosinophil count (9.24 ± 4.26% vs 5.32 ± 2.9%; p-value < 0.01) as well as AEC (823.335 ± 434.357/µl vs 485.128 ± 285/µl. 907; p-value < 0.01).
 Conclusion: The study demonstrated that CRS cases with tissue eosinophilia exhibit an elevated peripheral eosinophil count when compared to non-eosinophilic CRS.

An aggressive case of Warthin-like variant of papillary thyroid carcinoma (PTC)

Abstract Introduction/Objective Warthin-like variant of PTC is a rare subtype of PTC, characterized by papillary growth lined with oncocytic neoplastic cells and lymphocytic rich stroma in the stalks of the papillae. It is frequently associated with Hashimoto thyroiditis and has good prognosis due to lower risk of metastasis. An association with BRAF V600E mutation has been reported. Here we report an aggressive case of Warthin-like variant of PTC. Methods/Case Report A 33-year-old Hispanic female presented with a progressively expanding neck mass, difficulty swallowing, voice hoarseness, and neck pain. Ultrasound showed a 3.8 cm left thyroid nodule which on biopsy was positive for PTC. Laboratory tests were positive for anti-peroxidase and anti-thyroglobulin antibodies. A total thyroidectomy was performed. Grossly, the left thyroid lobe nodule was well-circumscribed, unencapsulated, and firm with solid homogenous gray-tan cut surface. Microscopically, the nodule consisted of large eosinophilic cells demonstrating characteristic PTC nuclear features, arranged in papillary structures with the cores packed with prominent lymphoplasmacytic infiltrate consistent with Warthin-like variant of PTC (figure). Separate sub-centimeter foci of PTC with similar features were identified in a background of chronic lymphocytic thyroiditis. Central and left neck dissection showed extensive lymph node metastasis which had features similar to the primary tumor but with less pronounced lymphoplasmacytic cores. The patient is currently 6-month post operation and is receiving iodine ablative therapy. Results (if a Case Study enter NA) NA Conclusion Molecular analysis of the tumor may aid in identifying molecular aberrations responsible for the aggressive nature in this case and potentially guide treatment.

Leiomyoma? Inflammatory myofibroblastic tumour as a mimic

Presentation: A 23-year-old female presented with a 7 cm fibroid with atypical features on MRI. There was minimal response to Goserelin (GnRH agonist for sex hormone suppression). The decision was made for hysterectomy. Pathology: Macroscopic examination showed a circumscribed whorled myometrial lesion resembling leiomyoma. Microscopic examination showed a spindle cell lesion predominantly consisting of bland fascicular leiomyoma-like areas and cellular storiform areas. However, the typical thick walled vessels of leiomyoma were notably absent. Other atypical features for leiomyoma included fasciitis-like areas, prominent lymphoplasmacytic infiltrate, and focally infiltrative borders. Immunohistochemistry demonstrated ALK positivity, and FISH studies confirmed ALK rearrangement. The features were of inflammatory myofibroblastic tumour (IMT) of the uterus. Discussion: Uterine IMT is a rare entity with low malignant potential. It may mimic leiomyoma on macroscopic and microscopic examination. The lack of thick walled vessels, fasciitis-like areas, and lymphoplasmacytic infiltrate raised suspicion of an alternative diagnosis to leiomyoma in this case. ALK is positive in the majority of cases thus, low threshold for ALK testing is advised in all uterine lesions that raise morphologic suspicion of IMT.

Prognosis and Survival of Medullary Carcinoma of the Breast

Medullary breast carcinoma (MBC) is a rare tumor, representing 3% to 5% of invasive breast carcinomas. The World Health Organization defines it as a well-circumscribed invasive tumor, composed of poorly differentiated cells, arranged in sheets, without gland formation and a scarce collagen stroma with the presence of a very prominent lymphoplasmacytic infiltrate.

Nanostring-based screening for tyrosine kinase fusions in inflammatory myofibroblastic tumors

Gene expression imbalances were measured for tyrosine kinase (TK) genes using Nanostring in 19 samples of inflammatory myofibroblastic tumor (IMT). All cases were immunohistochemically stained with anaplastic lymphoma kinase (ALK) and pan-tropomyosin-related-kinase (pan-Trk) antibodies. Five cases with imbalanced ALK expression, reported with Nanostring, were tested using fluorescence in situ hybridization (FISH); two cases with imbalanced neurotrophic tyrosine receptor kinase 3 (NTRK3) expression were tested using reverse transcription-polymerase chain reaction (RT-PCR). One case with imbalanced expression for ROS proto-oncogene 1 (ROS1) was tested using RNA sequencing and RT-PCR. TK fusions were detected in all cases with imbalanced TK expression. RNA sequencing detected a FN1–ROS1 fusion gene in an adult IMT case. IMT with ALK rearrangement showed myofibroblast-dominant features. IMT with ETV6–NTRK3 fusion showed prominent lymphoplasmacytic infiltration with scattered myofibroblasts. Pan-Trk IHC revealed only scattered positively stained cells in IMT with ETV6–NTRK3 fusion gene. ROS1-positive IMT showed myofibroblast-dominant features.

Lymphogranuloma venereum (LGV) of the anorectum: evaluation of clinicopathological associations and the utility of a novel RNA in-situ hybridisation stain.

Recent studies from multiple global regions have reported a resurgence of lymphogranuloma venereum (LGV) proctitis, which is caused by Chlamydia trachomatis (CT). LGV proctitis is histologically indistinguishable from other forms of sexually transmitted proctitis and is difficult to differentiate from inflammatory bowel disease. While immunohistochemical stains are available for syphilis, there is no commonly available stain for the tissue identification of CT. From 200 positive CT nucleic acid tests (NAT) from anorectal swabs, we identified 12 patients with biopsies collected from the distal colorectum or anus within 90days of the positive NAT. We collected basic demographic information and tabulated clinical and histological findings. We examined the performance of a novel RNA in-situ hybridisation (ISH) stain targeting CT 23s rRNA on these 12 cases and 10 controls from the anorectum. All 12 patients were male; nine were HIV+, two had concurrent gonococcal infection, one had concurrent syphilis and one had cytomegalovirus co-infection. The majority of biopsies (11 of 12) showed mild or moderate acute inflammation, had a prominent lymphoplasmacytic infiltrate (eight of 11) and lacked marked crypt distortion (10 of 10). The RNA ISH stain was positive in 10 of 12 cases (sensitivity 83%). One case showed equivocal staining. No controls showed definitive positive staining (specificity 100%). One had equivocal staining. Our series showed that anorectal LGV had similar histological findings to those of prior STI proctitis series predominantly comprised of syphilis. The novel RNA ISH stain was sensitive and specific and may show utility in differentiating types of STI proctitis.

P322 Impact of the presence of Epstein–Barr virus in intestinal mucosa of inflammatory bowel disease patients

Abstract Background To evaluate the importance of positive Epstein–Barr virus (EBV) status in intestinal biopsy in patients with inflammatory bowel disease (IBD), its association with active disease and immunosuppressive (IM) therapy and its influence on the clinical evolution of IBD. Methods We retrospectively analysed patients with IBD who were tested for EBV in intestinal mucosa between November 2009 and June 2017. Pathologists decided EBV testing based on the presence of severe histologic activity with/without prominent lymphoplasmacytic infiltrate or refractory disease to various treatments. We analysed phenotypic characteristics, previous treatments, active therapies at the time of EBV testing, EBV status by immunohistochemistry, presence of lymphoma, treatment decision making after EBV testing and subsequent clinical evolution based on hospital admissions and treatment escalation requirement. Results We included 56 patients, 28 with Crohn’s disease (CD) and 28 with ulcerative colitis (UC). The predominant phenotype of patients with CD was A2L3C1. Regarding patients with UC, 14 patient had left-sided and 14 extensive colitis. EBV was positive (EBV+) in 26 cases (46%), one of them associated with a lymphoproliferative disorder. EBV+ status was associated with clinically active disease (53.3% vs. 25%, p = 0.08); severe endoscopic (54.5% vs. 37.5%, p = 0.02) and severe histological activity (72.2% vs. 33.3%, p = 0.007) and the presence of a prominent lymphoplasmacytic infiltrate (68.8% vs. 16.7%, p < 0.0005). In addition, active steroid treatment, but not IM and/or biological therapy, at the time of EBV testing was associated with EBV+ status (61.5% vs. 33.3%, p = 0.03). Only the presence of a prominent lymphoplasmacytic infiltrate showed significant association with EBV+ in the multivariate analysis (p = 0001). IM therapy was de-escalated in 6/26 EBV-positive patients. In EBV- patients, IM treatment was escalated in 10/30. After a mean follow-up of 53.3 months, 17 patients required hospital admission and 26 escalation of therapy. Both risk of admissions and escalation of treatment during follow-up were higher in EBV+ patients (38.5% vs. 23.3%, p = 0.2; and 65.4% vs. 30%, p = 0.008, respectively). Only female sex was associated with a greater possibility of hospital admission and EBV+ with the need for treatment escalation (p = 0.03) in the multivariate analysis. None of the patients developed lymphoma during follow-up. Conclusion EBV+ status in intestinal mucosa is associated with histological activity. Prominent lymphoplasmacytic infiltrate is the only factor associated with EBV+ status independently of immunosuppression status. EBV+ is associated with subsequent poor clinical evolution and a greater need for escalation of IM therapy.

Rosai-Dorfman Disease of the Breast With Variable IgG4+ Plasma Cells: A Diagnostic Mimicker of Other Malignant and Reactive Entities.

Rosai-Dorfman disease (RDD) is an uncommon disorder, characterized by an atypical expansion of histiocytes which classically shows emperipolesis and immunoreactivity with S-100 protein. RDD affects the lymph nodes as well as extranodal sites; however, RDD of the breast is exceptionally rare. Herein, we describe the histopathologic features of 22 cases of RDD occurring in the breast, with an emphasis on the differential diagnosis. All cases were notable for an exuberant lymphocytic infiltrate with and without germinal center formation, and the majority (19/22) showed numerous plasma cells: 5 to 132/high-power field (HPF). IgG and IgG4 immunohistochemical stains were available for 13 cases; in no instance were criteria for IgG4-related sclerosing disease met, though in a single case the IgG4/IgG ratio was increased to 25%. Sclerosis was present in the majority of cases (18/22), and was frequently prominent. RDD cells showing emperipolesis were present in all cases (22/22), and ranged from rare (<1/50 HPF) to numerous (>50/50 HPF). Two of the cases in our series were initially misdiagnosed as inflammatory myofibroblastic tumor and plasma cell mastitis with granulomatous inflammation. As emperipolesis can be indistinct, the presence of stromal fibrosis and a prominent lymphoplasmacytic inflammatory infiltrate should prompt a careful search for the characteristic histiocytes, which can be aided by the use of S-100 immunohistochemistry.

Hepatic expression of programmed death-1 (PD-1) and its ligand, PD-L1, in children with autoimmune hepatitis: relation to treatment response.

Aim of the studyAutoimmune hepatitis (AIH) is characterized histologically by aggressive inflammation with interface hepatitis and prominent lymphoplasmacytic infiltration. Programmed death-1 (PD-1) is expressed on activated lymphocytes. Engagement of PD-1 by its ligand PD-L1 leads to cell apoptosis and death. We aimed to evaluate the immunohistochemical expression of PD-1 and PD-L1 in children with AIH, and its relation to treatment outcome.Material and methodsPre-treatment liver biopsies of 31 children with AIH were compared to 30 children with chronic hepatitis C virus (HCV) infection as a control group. PD-1 was evaluated in lymphocytes, while PD-L1 was evaluated in lymphocytes, hepatocytes, biliary epithelial cells, sinusoidal endothelial cells and Kupffer cells. All AIH patients received the standard treatment.ResultsThe mean PD-1 was significantly higher in AIH than HCV patients (29.19 ±18.5% vs. 15.2 ±10.1%; p = 0.002) while there was no statistically significant difference as regards PD-L1 on lymphocytes (p = 0.853). Neither PD-1 nor PD-L1 correlated with either liver fibrosis or the inflammatory activity (p > 0.05 for all). PD-1/PD-L1 ratio was significantly higher in AIH compared to HCV patients and in non-responder AIH patients compared to responders (46.9 vs. 6.58). PD-1 expression was comparable in both responders and non-responders (p = 0.813), while PD-L1 was significantly upregulated in responders (4.17 ±3.15% vs. 0.63 ±1.3%; p = 0.046). PD-L1 expression on hepatocytes, biliary epithelial cells, sinusoidal endothelial cells and Kupffer cells was comparable in AIH and HCV groups.ConclusionsPD-1/PD-L1 ratio, which reflects immune aggression, was significantly higher in AIH compared to HCV patients and in non-responder AIH patients compared to responders.

High-grade encapsulated papillary carcinoma of the breast is clinicopathologically distinct from low/intermediate-grade neoplasms in Chinese patients.

Encapsulated papillary carcinoma (EPC) of the breast is typically of low-to-intermediate grade (LTIG) with favorable prognosis. Rarely, high-grade (HG) EPC cases have been documented in recent years. Herein we compared the morphological, immunohistochemical, and clinical features of LTIG EPC to those of HG EPC. Of the 30 EPC patients, 25 were diagnosed as LTIG and five as HG (median age: 60 and 36 years, respectively); 80% of the HG EPCs exhibited predominantly solid architecture with prominent lymphoplasmacytic infiltrates, more crowded and thicker papillae, and greater stratification and irregular arrangement of malignant epithelial cells. Coexisting invasive components were observed in 32% and 80% of LTIG and HG cases, respectively. HG EPC was negative for hormone receptor staining. Additionally, 48% of LTIG EPC cases were moderately positive for human epidermal growth factor receptor 2 (Her-2) immunostaining (2+); among them, one case showed Her-2 gene amplification by fluorescence in situ hybridization. The basal-like markers cytokeratin 5/6 and epidermal growth factor receptor were detected in two and five HG cases, respectively. HG EPC was also characterized by a significantly high Ki-67 index (median: 85%, P<0.001). No local recurrence or distant metastasis was noted during the follow-up. HG EPC typically exhibited a solid architecture with a concurrent invasive component as well as a triple-negative and basal-like immunophenotype in young women. HG EPC might be indicative of high proliferative activity and potential aggressiveness.

IgG4-Related Lung Disease Associated with Usual Interstitial Pneumonia.

We report a case of immunoglobulin(Ig)G4-related disease with the radiologic and histopathological manifestations resembling usual interstitial pneumonia (UIP). The patient was a 62-year-old man who presented with progressive dyspnea of insidious onset. High resolution computed tomography of the chest showed lower-lobe predominant peripheral reticulation and traction bronchiectasis but no honeycomb change. Microscopic examination of the surgical lung biopsy showed characteristic features of UIP including architectural distortion by fibrosis with peripheral and paraseptal accentuation, scattered fibroblast foci and microscopic honeycomb change. In addition there were prominent multifocal lymphoplasmacytic infiltrates with a marked increase of IgG4-positive plasma cells (79 per high power field in hot spots) and high IgG4/IgG ratio (up to 67%). The serum IgG4 level was elevated at 760 mg/dl (reference range 9-89), with normal levels for the other IgG subclasses and negative serologic markers for autoimmune diseases. The patient’s symptoms improved significantly with oral corticosteroid treatment.

Lymphoepithelioma-Like Hepatocellular Carcinoma: Report of Three Cases and Review of Literature

Lymphoepithelioma-like carcinomas (LELCs) are carcinomas which show histologic similarities to lymphoepithelioma (AKA nasopharyngeal carcinoma) and prominently feature a lymphoid-rich stroma with tumor-infiltrating lymphocytes. LELCs have been described in a number of different organ systems, are often associated with Epstein-Barr virus (EBV) infection, and have been reported to carry favorable prognoses when compared to classic carcinomas of these organ systems. LELCs of the liver are exceedingly rare. Here, we report three cases of lymphoepithelioma-like hepatocellular carcinoma (HCC) in one female and two male patients. All three carcinomas were composed of a population of malignant cells with focal to diffuse positivity for HepPar-1, as well as a prominent lymphoplasmacytic infiltrate intimately associated with the malignant cells. In two cases investigated by immunohistochemistry, the lymphoid population contained a prominent CD3 + T-cell population which consisted of CD4 + lymphocytes and CD8 + cytotoxic T cells, which also showed staining for T-cell intracellular antigen-1 (TIA-1). Chromogenic in situ hybridization for EBV-encoded RNA (EBER CISH) was negative in both the malignant cells and the lymphoid population in all three cases. Two patients who underwent surgical resection are alive without recurrence at 38 and 26 months after surgery. The third patient treated by chemoembolization died 31 months after the diagnosis. J Med Cases. 2015;6(7):297-303 doi: http://dx.doi.org/10.14740/jmc2106w